Matrix metalloproteases (MMPs) create havoc both outside and inside a cell to pave the way for tumorigenesis, based on findings from Derek Radisky, Mina Bissell (Berkeley Lab, Berkeley, CA), and colleagues.
MMPs are known to support cancer progression by their ability to degrade the matrix and clear the way for invasion and metastasis. Bissell's lab now shows that MMP-3 can also stimulate genomic instability, a key tumor characteristic, in mammary epithelial cells.
The genomic instability stems from mitochondrial production of the reactive oxygen species (ROS) superoxide, which altered the genotype and phenotype of mammary epithelial cells. The authors show that ROS are sufficient to reproduce the effects of MMP treatment, and that quenching ROS prevents MMP-3–induced genomic rearrangements and cell motility. The authors are now investigating the link between ROS and motility.
Superoxide is made in response to the induction of an overactive splice variant of the Rac1 GTPase in MMP-treated cells. Expression of this variant, called Rac1b, induced ROS in the absence of MMPs. The MMP-induced cell motility that accompanies invasiveness was prevented by silencing Rac1b, which might be a new target for antitumor therapies. It is unclear how MMPs cause the alternative splicing of Rac1. Perhaps β-catenin, which moves to the nucleus upon E-cadherin cleavage by MMPs, affects splicing as well as transcription.